Clinical efficacy of temocillin

Sir, Livermore and Tulkens1 state that published clinical data on temocillin's use in severe sepsis and nosocomial pneumonia remain scanty. This is particularly relevant when extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are involved, as therapeutic options are limited.2 Here we present clinical data on the use of temocillin in severe sepsis related to infections of the biliary and urinary tracts, as well as nosocomial pneumonia and diverticulitis. Five patients had infections with Enterobacteriaceae producing ESBLs (three Klebsiella pneumoniae, one Escherichia coli and one dual infection with both K. pneumoniae and E. coli, both ESBL-positive). One patient had ventilator-associated pneumonia (VAP) and bacteraemia: Enterobacter aerogenes (a derepressed mutant with constitutive production of AmpC chromosomal cephalosporinase) and ESBL-negative K. pneumoniae were isolated from sputum, and a fully susceptible Proteus mirabilis from blood (Table 1). Isolates were identified using Phoenix Automated Microbiology System (BD Diagnostic Systems, Sparks, MD, USA) methodology and ESBL/AmpC production was confirmed using Phoenix and/or combination disc methodology. Temocillin MICs were determined by Etest (AB Biodisk, Solna, Sweden). Patients with infections due to Enterobacteriaceae producing ESBLs or AmpC β-lactamase and treated with temocillin aAMK, amikacin; AMP, ampicillin; ATM, aztreonam; LEX, cefalexin; CTX, cefotaxime; CAZ, ceftazidime; CXM, cefuroxime; CIP, ciprofloxacin; AMC, co-amoxiclav; SXT, co-trimoxazole; GEN, gentamicin; MEC, mecillinam; MTZ, metronidazole; NOR, norfloxacin; TZP, piperacillin/tazobactam. bTemocillin breakpoints (CLSI): susceptible, ≤16 mg/L; resistant, >32 mg/L. cESBL-producing isolate. dDerepressed mutant with constitutive production of AmpC chromosomal cephalosporinase. Patients with infections due to Enterobacteriaceae producing ESBLs or AmpC β-lactamase and treated with temocillin aAMK, amikacin; AMP, ampicillin; ATM, aztreonam; LEX, cefalexin; CTX, cefotaxime; CAZ, ceftazidime; CXM, cefuroxime; CIP, ciprofloxacin; AMC, co-amoxiclav; SXT, co-trimoxazole; GEN, gentamicin; MEC, mecillinam; MTZ, metronidazole; NOR, norfloxacin; TZP, piperacillin/tazobactam. bTemocillin breakpoints (CLSI): susceptible, ≤16 mg/L; resistant, >32 mg/L. cESBL-producing isolate. dDerepressed mutant with constitutive production of AmpC chromosomal cephalosporinase. Infection completely resolved on temocillin in all but two cases, patients 4 and 5. Patient 4 developed a diverticular abscess that was drained radiologically 2 months later, and K. pneumoniae, E. coli (both ESBL-positive), Enterococcus faecium and yeasts were cultured from pus. She was initially treated with meropenem [1 g intravenously (iv) once daily] for 10 days, followed by de-escalation to temocillin (1 g iv thrice weekly with dialysis) and metronidazole (400 mg orally once daily). Definitive surgery was not possible owing to co-morbidities, and temporary withdrawal of temocillin had previously resulted in septic deterioration. She is currently stable on temocillin (1 g iv thrice weekly) and metronidazole (400 mg orally once daily) with a long-term drain in situ. Patient 5 presented with acute cholangitis on a background of primary biliary cirrhosis, for which she was awaiting liver transplantation. Blood cultures from admission grew an ESBL-producing K. pneumoniae. Inducible AmpC was not detected on induction testing. The isolate was susceptible to several antibiotics including temocillin (MIC 16 mg/L) and showed intermediate susceptibility to piperacillin/tazobactam (MIC 64/4 mg/L) (Table 1). She was treated with temocillin (1 g iv once daily), a lower dose regimen being applied due to renal impairment [estimated glomerular filtration rate (eGFR) 27 mL/min]. The patient rapidly improved over the next 48 h (temperature 37.2°C and C-reactive protein 75 mg/L compared with 38.7°C and 145 mg/L, respectively, on admission). During this time, her renal function improved (eGFR 103 mL/min) and her temocillin dose was increased to 1 g twice daily accordingly. On the fourth day of temocillin treatment she deteriorated and repeat blood cultures again grew an ESBL-producing K. pneumoniae. In contrast to the initial isolate, this breakthrough isolate was of only intermediate susceptibility to temocillin (MIC 32 mg/L) and resistant to mecillinam and piperacillin/tazobactam (MIC > 64/4 mg/L). The patient was changed from temocillin to ertapenem (1 g iv once daily), and made a good recovery. To our knowledge, this is the first reported case of breakthrough bacteraemia on temocillin treatment. One factor that may have predisposed to the loss of susceptibility in this patient was her renal function, which, having initially been sufficiently impaired to merit once daily dosing, rapidly improved and could therefore have resulted in temocillin levels falling and remaining below the MIC for protracted periods. In addition, biliary concentrations of temocillin would have been particularly compromised because the biliary tree was severely damaged due to primary biliary cirrhosis. The simultaneous acquisition of resistance to mecillinam and piperacillin/tazobactam is particularly worrying, and might reflect mediation by a common mechanism or genetic element. Two other patients were treated with temocillin for infections caused by E. coli not producing ESBLs or AmpC. The first patient was a 78-year-old lady who was admitted to the Intensive Therapy Unit with severe urosepsis complicated by acute renal failure. She responded very well to a single dose of temocillin (1 g iv) and a 2 day course of gentamicin (2 mg/kg iv once daily). A fully susceptible E. coli was cultured from urine and treatment was de-escalated to co-amoxiclav (1.2 g iv thrice daily) for a further 4 days. The second patient was a 67-year-old lady with an intra-abdominal collection following biliary reconstruction, who was treated with temocillin (1 g iv twice daily) and metronidazole (500 mg iv thrice daily). She developed VAP with Pseudomonas aeruginosa on the fourth day of treatment; amikacin (15 mg/kg iv once daily) was added and temocillin switched to meropenem (1 g iv thrice daily). The patient subsequently deteriorated and died. No side effects attributable to temocillin and no cases of Clostridium difficile infection were reported in this series of patients. These data illustrate the potential clinical usefulness of temocillin, particularly as a directed-spectrum alternative to the carbapenems in infection due to ESBL/AmpC-positive Enterobacteriaceae. Comparative clinical trials are now needed. No specific funding has been received. Data have been generated as part of the routine work of the Royal Free Hampstead NHS Trust. None to declare